EP0418004A2 - Agent préventif et thérapeutique pour l'hépatite - Google Patents

Agent préventif et thérapeutique pour l'hépatite Download PDF

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Publication number
EP0418004A2
EP0418004A2 EP90309859A EP90309859A EP0418004A2 EP 0418004 A2 EP0418004 A2 EP 0418004A2 EP 90309859 A EP90309859 A EP 90309859A EP 90309859 A EP90309859 A EP 90309859A EP 0418004 A2 EP0418004 A2 EP 0418004A2
Authority
EP
European Patent Office
Prior art keywords
hepatitis
oil
preventive
therapeutic agent
fat emulsion
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP90309859A
Other languages
German (de)
English (en)
Other versions
EP0418004A3 (en
EP0418004B1 (fr
Inventor
Masahiro C/O Chuo Kenkyusho Of Watanabe
Kazumasa C/O Chuo Kenkyusho Of Yokoyama
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsubishi Tanabe Pharma Corp
Taisho Pharmaceutical Co Ltd
Original Assignee
Green Cross Corp Japan
Taisho Pharmaceutical Co Ltd
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Filing date
Publication date
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Application filed by Green Cross Corp Japan, Taisho Pharmaceutical Co Ltd filed Critical Green Cross Corp Japan
Publication of EP0418004A2 publication Critical patent/EP0418004A2/fr
Publication of EP0418004A3 publication Critical patent/EP0418004A3/en
Application granted granted Critical
Publication of EP0418004B1 publication Critical patent/EP0418004B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to a novel use of a fat emulsion containing a compound having prostaglandin E1 activities, more particularly to a preventive and/or therapeutic agent for hepatitis using such a fat emulsion.
  • Fulminant hepatitis is developed at the time when acute hepatitis has been proceeded (rate of development being about 2%). Fulminant hepatitis is caused by hepatic virus etc. and is typified by rapid development of symptoms of hepatic insufficiency. A high percentage of the patients suffering from this disease die from hepatic coma in some to 10 days after development of the symptoms.
  • a fat emulsion containing a compound having prostaglandin E1 (hereinafter referred to as PGE1) activities is not only potent against fulminant hepatitis but also more widely useful for the treatment of many types of hepatitis.
  • PGE1 prostaglandin E1
  • the preventive and/or therapeutic agent for hepatitis comprises a fat emulsion containing a compound having PGE1 activities.
  • the compounds having PGE1 activities usable in the present invention include all the compounds which have PGE1 activities and are pharmaceutically acceptable ones.
  • PGE1 and its derivatives are typical examples.
  • the PGE1 derivatives usable in this invention are the ones which have PGE1 activities and are suited for use as a pharmaceutical component.
  • the PGE1 derivatives disclosed in U.S. Patent 4,849,451 and Japanese Patent Application (Laid-open) No. 59-­216820 are preferred.
  • PGE1 and its derivatives are those represented by the general formula wherein R denotes hydrogen and an alkyl group having 1 to 30 carbon atoms respectively.
  • the alkyl group in the above general formula may be of either straight chain or branched chain.
  • the number of its carbon atoms is 1 to 30, preferably 1 to 15 and more preferably 3 to 10.
  • Examples of such alkyl groups include methyl, ethyl n-propyl, isopropyl, n-­butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-­heptyl, n-octyl, n-nonyl and n-decyl.
  • a fat emulsion containing a compound having PGE1 activities, which constitutes active ingredient of the preventive and therapeutic agent for hepatitis according to the present invention may comprise, for instance, 5 to 50, preferably 10 to 20% (W/V) of a vegetable oil, 1 to 50, preferably 5 to 30 parts by weight of phospholipid for 100 parts by weight of the vegetable oil, a proper quantity of water, and an effective quantity of a compound having PGE1 activities.
  • the fat emulsion may be added, if necessary, with 0.3% (W/V) or less of an emulsifier adjuvant, 5% (W/V) or less of a stabilizer, a polymeric substance as stabiliz­ing adjuvant in an amount of 0.1 to 5, preferably 0.5 to 1 parts by weight to 1 part of the compound having PGE1 activities (i.e. PGE1 or PGE1 derivative), and 0.1 - 10% (W/V) of an isotonizing agent (for example, glycerin and glucose).
  • an isotonizing agent for example, glycerin and glucose
  • the content of the compound having PGE1 activities in the fat emulsion can be properly varied depending on the form of emulsion, the way of administration, etc., but usually said compound is contained in an amount of 0.2 to 100 ⁇ g/ml in the emulsion.
  • the vegetable oil to be added to said fat emulsion include soybean oil, sesame oil, castor oil, cottonseed oil and olive oil, and soybean oil is preferred. It is more preferred to use a highly purified soybean oil, particularly preferably a high-­purity soybean oil (purity: 99.9% or above as tri-, di- and mono-glyceride) obtained by further purifying the commonly purified soybean oil by steam distillation or other like means.
  • phospholipid there can be used purified phospholipid such as egg yolk phospholipid and soybean phospholipid, and it can be prepared by ordinary fractionation method using an organic solvent. For instance, crude egg yolk phospholipid is dissolved in a cold n-hexane-acetone mixed solvent, slowly adding acetone thereto with stirring, followed by filtering-out of insolubles, and after repeating this operation once more, the solvent is distilled off to obtain the desired purified phospholipid.
  • the thus obtained phospholipid mainly consists of phosphatidyl choline and phosphatidyl ethanolamine. It also contains other phospholipids such as phosphatidyl inositol, phosphatidyl serine, sphingomyelin and the like in smaller quantities.
  • the emulsifying adjuvant includes fatty acids of 6 to 22, preferably 12 to 20 carbon atoms which are pharmaceutically acceptable. These fatty acids may be of either straight chain or branched chain, but straight-chain stearic acid, oleic acid, linolic acid, palmitic acid, linolenic acid, myristic acid and the like are preferred. It is also possible to use their pharmaceutically acceptable salts such as alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salts (calcium salt, etc.).
  • the stabilizer includes cholesterols and phosphatidic acid which are pharmaceutically usable, and are used in an amount of 0.5, preferably 0.1% (W/V) and in an amount of 5, preferably 1% (W/V), respectively.
  • the polymeric substance includes albumin, dextran, vinyl polymer, nonionic surfactant, gelatin and hydroxyethyl starch, and preferred types of albumin, vinyl polymers and nonionic surfactants usable as polymeric substance are as follows.
  • Albumin should be of the human origin in consideration of antigenicity.
  • a typical example of vinyl polymers is polyvinylpyrrolidone.
  • nonionic surfactant there can be used polyalkylene glycol (for example, polyethylene glycol having an average molecular weight of 1,000 to 10,000, preferably 4,000 to 6,000), polyoxalkylene copolymers (for example, polyoxyethylene-polyoxypropylene copolymer having an average molecular weight of 1,000 to 20,000, preferably 6,000 to 10,000), hardened castor oil polyoxyalkylene derivatives [for example, hardened castor oil polyoxyethylene-(40), -(20) and -(100) ether], and castor oil polyoxyalkylene derivatives [for example, castor oil polyoxyethylene-(20), -(40) and -(100) ether].
  • polyalkylene glycol for example, polyethylene glycol having an average molecular weight of 1,000 to 10,000, preferably 4,000 to 6,000
  • polyoxalkylene copolymers for example, polyoxyethylene-polyoxypropylene copolymer having an average molecular weight of 1,000 to 20,000, preferably 6,000 to
  • Glycerin or glucose used as isotonizing agent in this invention is a pharmaceutically acceptable one.
  • the fat emulsion used in the present invention can be prepared by the various methods. For example, it can be produced in the following way.
  • a vegetable oil preferably soybean oil
  • phospholipid preferably phospholipid
  • a compound having PGE1 activities and other additives such as mentioned above are mixed and added with a necessary amount of water.
  • This solution is homogenized by a commonly used homogenizer (such as a pressure-jet type homogenizer or an ultrasonic homogenizer) to prepare an oil-in-water type emulsion, whereby a desired fat emulsion is produced.
  • the thus produced fat emulsion may be further added with a stabilizer, isotonizing agent and other additive(s) if necessary for the reasons relating to formulation.
  • the preventive and therapeutic agent for hepatitis of this invention comprising said fat emulsion is usually administered by intravenous injection, continuous drip infusion, or in other appropriate ways.
  • the agent is generally given at a dose of about 0.1 to 20 ⁇ g/kg body weight, preferably 1 to 10 ⁇ g/kg body weight, in terms of quantity of active ingredient, in one administration for adults, but the dose may be properly adjusted according to the condition of the patient, the region of application, etc.
  • the preventive and therapeutic agent for hepatitis according to the present invention is considered to be particularly effective for the treatment of fulminant hepatitis.
  • the present agent has potenties for various types of hepatitis; it is not only utility against fulminant hepatitis but also effective for the treatment of viral hepatitis, alcoholic hepatitis, drug-induced hepatitis, acute and chronic hepatitis, and useful for the prevention of hepatic insufficiency, hepatocirrhosis and other hepatic troubles.
  • the preventive and therapeutic agent for hepatitis of this invention is capable of retaining its efficacy for a long time in the living body and can produce a sufficient action with a small dose. This effect is more remarkable than the PGE1 cyclodextrin clathrate.
  • the present agent therefore is of extremely high clinical utility for the prevention and therapeutics of heptatitis.
  • This crude emulsion was passed through Manton-­Gaulin homogenizer under high pressure, whereby a fat emulsion containing homogenized, extremely fine PGE1 particles could be obtained (this fat emulsion is hereinafter referred to as PGE1-lipo).
  • This emulsion had an average particle diameter of 0.2 to 0.4 ⁇ .
  • a fat emulsion was prepared in the same way as in Example 1 except that 0.15 g of sodium oleate was used in place of 0.15 g of sodium palmitate and 0.15 g of phosphatidic acid.
  • P. acnes which is a Gram-positive anaerobe
  • LPS lipopolysaccharide
  • PGE1-lipo prepared in Example 1 was intravenously injected (tail vein) (at a dose of 0.25 ⁇ g/mouse and 0.5 ⁇ g/mouse in terms of the quantity of PGE1) to the test mice just before giving LPS, and the rate of survival of the mice after the lapse of 24 hours was examined.
  • cyclodextrin clathrate of PGE1 (PGE1-CD) was intravenously injected (at a dose of 0.5 ⁇ g/mouse in terms of quantity of PGE1) in the same way as described above, and the survival rate was compared with another control group to which a physiological saline solution was given.
  • Table 1 The results are shown in Table 1.
  • Table 1 Specimen Rate of survival (%) 10 hrs aftrer giving LPS 24 hrs. after giving LPS Physiological saline solution (control) 20 10 PGE1-lipo (0.25 ⁇ g/animal) 50 30 PGE1-lipo (0.5 ⁇ g/animal) 80 60 PGE1-CD (0.5 ⁇ g/animal) 40 10 LPS was administered 7 days after giving P. acnes , and each specimen was administered just before giving LPS.
  • Endotoxin is considered to play an important role against a rapid development of symptoms of hepatic insufficiency.
  • Test Example 1 shows, by administering heated-killed P. acnes, monocitosis is induced in the liver. A further administration of endotoxin causes apparent necrosis of the liver, which proceeds to death. The present drug showed very strong life-saving effects against such hepatic insufficiency.
  • hepatic homogenate supernatant fraction (4 mg/ml) treated with sodium 2,4,6-­trinitrobenzenesulfonate (TNP) was administered along with an equal amount of Freund complete adjuvant (FCA) subcutaneously to the heels of guinea pigs (body weight: 400-500 g; divided into groups of 10). 2 weeks thereafter, 5 x 106 TNP-treated liver cells were given into the mesentric vein to induce immunological hepatic insufficiency cytotoxic trouble.
  • FCA Freund complete adjuvant
  • PGE1-lipo prepared in Example 1 was administered intravenously (0.05 ⁇ g/animal, 0.1 ⁇ g/animal and 0.2 ⁇ g/animal in terms of quantity of PGE1) just before giving the TNP-­treated liver cells, and 24 hours thereafter, the effect on rise of serum GOT and GPT was investigated.
  • a physiological saline solution was given to the comparative control group in the similar way. The results are shown in Table 2.
  • GOT of the normal (non-­treated) guina pigs was 48 ⁇ 10 (IU/l) and GPT thereof was 45 ⁇ 7 (IU/l).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP90309859A 1989-09-11 1990-09-10 Agent préventif et thérapeutique pour l'hépatite Expired - Lifetime EP0418004B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP235386/89 1989-09-11
JP1235386A JPH03101622A (ja) 1989-09-11 1989-09-11 肝炎予防治療剤

Publications (3)

Publication Number Publication Date
EP0418004A2 true EP0418004A2 (fr) 1991-03-20
EP0418004A3 EP0418004A3 (en) 1991-12-27
EP0418004B1 EP0418004B1 (fr) 1995-08-02

Family

ID=16985315

Family Applications (1)

Application Number Title Priority Date Filing Date
EP90309859A Expired - Lifetime EP0418004B1 (fr) 1989-09-11 1990-09-10 Agent préventif et thérapeutique pour l'hépatite

Country Status (8)

Country Link
US (1) US5091417A (fr)
EP (1) EP0418004B1 (fr)
JP (1) JPH03101622A (fr)
KR (1) KR910005872A (fr)
CA (1) CA2024965A1 (fr)
DE (1) DE69021304T2 (fr)
DK (1) DK0418004T3 (fr)
ES (1) ES2075161T3 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0424156A2 (fr) * 1989-10-20 1991-04-24 R-Tech Ueno Ltd. Traitement de la maladie hépatobiliaire avec des dérivés de la 15-céto-prostaglandine
EP0455448A2 (fr) * 1990-05-01 1991-11-06 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Traitement de maladies de pancréas à l'aide de dérivés 15-céto prostaglandines
WO1997029752A1 (fr) * 1994-12-22 1997-08-21 Alcon Laboratories, Inc. Compositions a base de prostaglandine, stables lors de leur stockage
EP0857484A1 (fr) * 1995-09-13 1998-08-12 Nippon Shinyaku Company, Limited Preparation lyophilisee contenant de la pge 1? et son procede de production
US6011062A (en) * 1994-12-22 2000-01-04 Alcon Laboratories, Inc. Storage-stable prostaglandin compositions

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5348764A (en) * 1992-10-06 1994-09-20 Yasuhiro Yokoshima Method for impregnating a lining material with a hardenable resin
JP4044967B2 (ja) * 1997-02-10 2008-02-06 小野薬品工業株式会社 １１，１５−ｏ−ジアルキルプロスタグランジンｅ誘導体、それらの製造方法およびそれらを有効成分として含有する薬剤
US6553644B2 (en) 2001-02-09 2003-04-29 International Business Machines Corporation Fixture, carrier ring, and method for processing delicate workpieces
TW200800265A (en) * 2006-02-09 2008-01-01 Schering Corp Combinations comprising HCV protease inhibitor(s) and HCV polymerase inhibitor(s), and methods of treatment related thereto

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0097481A1 (fr) * 1982-06-18 1984-01-04 Taisho Pharmaceutical Co. Ltd Emulsion contenant de la prostaglandine E1 et sa méthode de préparation
EP0132027A1 (fr) * 1983-05-20 1985-01-23 Taisho Pharmaceutical Co. Ltd Une émulsion grasse contenant une prostaglandine
EP0150732A2 (fr) * 1984-01-12 1985-08-07 Green Cross Corporation Composition de prostaglandine émulsifiée au phospholipide

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60181068A (ja) * 1984-02-29 1985-09-14 Teijin Ltd ６−置換プロスタグランジンｅ↓１類およびその製造法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0097481A1 (fr) * 1982-06-18 1984-01-04 Taisho Pharmaceutical Co. Ltd Emulsion contenant de la prostaglandine E1 et sa méthode de préparation
EP0132027A1 (fr) * 1983-05-20 1985-01-23 Taisho Pharmaceutical Co. Ltd Une émulsion grasse contenant une prostaglandine
EP0150732A2 (fr) * 1984-01-12 1985-08-07 Green Cross Corporation Composition de prostaglandine émulsifiée au phospholipide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STN FILE SERVICE (karlsruhe), FILE BIOSIS AN 89:200844; Y. UEDA et al.: "Protective effect of prostaglandin E1 "PGE1" on energy metabolism and res function in the ischemically damaged canine liver", & LIVER 9 (1), 1989 6-13 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0424156A2 (fr) * 1989-10-20 1991-04-24 R-Tech Ueno Ltd. Traitement de la maladie hépatobiliaire avec des dérivés de la 15-céto-prostaglandine
EP0424156A3 (en) * 1989-10-20 1992-04-22 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Treatment of hepatobiliary disease with 15-keto-prostaglandin compounds
EP0455448A2 (fr) * 1990-05-01 1991-11-06 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Traitement de maladies de pancréas à l'aide de dérivés 15-céto prostaglandines
EP0455448A3 (en) * 1990-05-01 1992-07-08 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Treatment of pancreatic disease with 15-keto-prostaglandin compounds
US5164415A (en) * 1990-05-01 1992-11-17 K.K. Ueno Seiyaku Oyo Kenkyujo Treatment of pancreatic disease with 15-keto-prostaglandin compounds
WO1997029752A1 (fr) * 1994-12-22 1997-08-21 Alcon Laboratories, Inc. Compositions a base de prostaglandine, stables lors de leur stockage
US5849792A (en) * 1994-12-22 1998-12-15 Alcon Laboratories, Inc. Storage-stable prostaglandin compositions
AU700574B2 (en) * 1994-12-22 1999-01-07 Alcon Laboratories, Inc. Storage-stable prostaglandin compositions
US6011062A (en) * 1994-12-22 2000-01-04 Alcon Laboratories, Inc. Storage-stable prostaglandin compositions
EP0857484A1 (fr) * 1995-09-13 1998-08-12 Nippon Shinyaku Company, Limited Preparation lyophilisee contenant de la pge 1? et son procede de production
US5977172A (en) * 1995-09-13 1999-11-02 Nippon Shinyaku Co., Ltd. PGE1 -containing-freeze dried preparation and process for the production thereof
EP0857484A4 (fr) * 1995-09-13 2000-12-06 Nippon Shinyaku Co Ltd Preparation lyophilisee contenant de la pge1- et son procede de production

Also Published As

Publication number Publication date
KR910005872A (ko) 1991-04-27
EP0418004A3 (en) 1991-12-27
EP0418004B1 (fr) 1995-08-02
ES2075161T3 (es) 1995-10-01
CA2024965A1 (fr) 1991-03-12
US5091417A (en) 1992-02-25
DK0418004T3 (da) 1995-09-18
JPH03101622A (ja) 1991-04-26
DE69021304D1 (de) 1995-09-07
DE69021304T2 (de) 1996-01-18

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